The present invention relates to a clinically highly useful pharmaceutical preparation having non-N-methyl-D-aspartate (non-NMDA) excitatory amino acid receptor antagonistic action, for example 2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonistic action, which is useful specifically as an agent for preventing, treating and ameliorating nerve degeneration diseases, more specifically 1) acute nerve degeneration after cerebral ischemia and cerebrospinal injuries, 2) chronic nerve degeneration diseases such as Alzheimer""s disease, Parkinson""s disease, amyotrophic lateral sclerosis (ALS) or Huntington""s chorea, 3) epilepsy, 4) pain, 5) spastic paralysis or 6) demyelinating diseases such as multiple sclerosis (MS), encephalomyelitis, Guillain Barre syndrome, Marchiafava Bignami disease, Devic disease, Balo disease, HIV or HTLV myelopathy, and leukoencephalopathy.
Amino acids such as glutamic acid and aspartic acid are known as excitatory amino acids (hereinafter abbreviated to EAAs) governing excitatory neurotransmission in the central nervous system. It is reported that excessive release or accumulation of these EAAs in synaptic clefts in nerve cells causes abnormal excitation in the central nervous system, thus leading to nerve degeneration, mental disorders and motor function disorders observed after cerebral ischemia, traumas in the head, cerebrospinal injuries, Alzheimer""s disease, Parkinson""s disease, amyotrophic lateral sclerosis, Huntington""s chorea, AIDS-related nerve disorder, epilepsy or low-oxygen condition. It is also reported that the abnormal excitation in the central nervous system is related to pain and spasm. Further, it is reported that EAAs are involved in nerve disorders caused by toxins contained in foods. Accordingly, a chemical regulating the abnormal functions of EAAs is considered useful as a therapeutic agent for nerve degeneration and spiritual disorders. Furthermore, it is also considered useful as an analgesic for pain etc. originating in chronic pain, migraine, cancerous pain, diabetic nerve disorders, and as a muscle relaxant (Lipton and Rosenberg, N. Eng. J. Med., 330, 613, 1994, Lees, CNS Drugs, 5, 51, 1996, Turski et al., J. Pharmacol. Exp. Ther., 260, 742, 1992). The action of EAA is demonstrated via a glutamate receptor that is a specific receptor present in presynaptic membrane and postsynaptic membrane. This receptor is classified on the basis of electrophysiological or neurochemical properties into (1) N-methyl-D-aspartic acid (NMDA) receptor, (2) non-NMDA receptor, that is, 2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor and kainic acid receptor, and (3) metabolism antagonism type glutamate receptor.
EAAs activate the above glutamate receptor and transmits excitation in the central nervous system. Further, it is reported that nerve disorders occur when excess EAA, NMDA, AMPA or kainic acid acts on nerve cells (Meldrum, B., Brain Res. Reviews, 18, 293, 1993). It is known that a compound having AMPA receptor antagonistic action shows a nerve-protecting action in a model with ischemia. It is reported that a competitive inhibitor, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f-]quinoxaline (referred to hereinafter as NBQX) is effective in an experimental animal model with cerebral ischemia (Sheardown et al., Science, 247, 571, 1990). Further, a non-competitive inhibitor GYKI 52466 (1-(amino-phenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzoazepine hydrochloride) exerts a nerve-protecting action in a rat model with cerebral ischemia (Le Peillet et al., Brain Research, 571, 115, 1992). These reports suggest that the AMPA inhibitor inhibits nerve degeneration after cerebral ischemia. The compound having AMPA receptor antagonistic action is reported as follows. WO 96/10023 and WO 94/25469 disclose quinoxalinedione compounds having a competitive inhibitory action on AMPA receptors. Further, WO 95/01357, WO 97/43276 and DE 19643037 disclose compounds having non-competitive inhibitory action on AMPA receptors.
Cerebral ischemia is a highly frequent acute degeneration disease in the central nervous system. This disease is caused by occlusion of vessels for supplying blood to the brain or by systemic circulatory disturbance such as cardiac standstill, and irreversible necrosis of nerve cells in the brain is caused by shortage of blood supplied. As a result, disturbance such as motor disturbance including paralysis in hands and legs, hindrance of sensibility, abnormal behavior, etc. is brought about as sequelae. Therapy for preventing necrosis of brain nerve cells at an acute stage from a few hours to a few days after onset is very important for relieving sequelae. Further, there is an attempt at recovering blood stream at a stage called an ultra-acute stage, but symptomatic treatment against brain edema and general control are merely conducted, and there is no established method effective in many cases.
Traumas in the head and spinal injuries are acute degeneration diseases in cells in the central nervous system, and are often accompanied by cerebral ischemic conditions. These diseases cause paralysis, hindrance of sensibility, abnormal behavior etc. as sequelae. After onset, protection of the cells by early therapy is important, but therapeutic methods conducted so far are symptomatic treatment such as inhibition of edema and surgical removal of damaged sites, which does not necessarily lead to a reduction in the sequelae.
Chronic nerve degeneration diseases such as Alzheimer""s disease, Parkinson""s disease, amyotrophic lateral sclerosis and Huntington""s chorea occur due to degeneration of nerve cells in the brain and spinal cord. Detailed causes for these diseases remain unclear, and no therapeutic method is established for inhibiting the degeneration of nerve cells in these diseases.
Epilepsy is a repetitive spasmodic disorder caused by abnormal excitation of cerebral nerve cells and may be accompanied by hindrance of consciousness or hindrance of sensibility. For therapy of epilepsy, administration of an anti-spastic agent is conducted, but there may occur severe hepatic disturbance or side effects such as poor-regeneration anemia, skin mucous membrane eye syndrome etc.
Pain (sharp pain) is a clinical symptom caused by various diseases. For treatment of pain, administration of an antalgic is usually conducted, but there is a certain pain not responding to a conventional antalgic.
Spastic paralysis is a clinical symptom caused by promotion of abnormal muscular tension, to cause motor disturbance. For treatment of spastic paralysis, a muscular relaxant is administered, but side effects such as drowsiness, sense of exhaustion and sedative action occur highly frequently.
Demyelinating diseases are diseases caused by various causes. These diseases are accompanied by paresthesia, pain, spastic paralysis, micturition disturbance etc. Among these diseases, multiple sclerosis that is a demyelinating disease in the central nervous system is a recurring progressive disease, and there is no established therapeutic method.
There is no practical therapeutic, ameliorating or preventive agent for acute nerve degeneration diseases after cerebral ischemia and cerebrospinal injuries, chronic nerve degeneration disease, epilepsy, pain, spastic paralysis, and demyelinating disease by use of non-NMDA excitatory amino acid receptor antagonistic action, particularly AMPA receptor antagonistic action, and its development is desired.
The present inventors paid attention to compounds having non-NMDA excitatory amino acid receptor antagonistic action, particularly AMPA receptor antagonistic action, and made extensive study. As a result, they succeeded in synthesizing a novel heterodiazinon compound represented by the formula: 
as well as a pharmacologically acceptable salt thereof. Further, they found that these compounds have an excellent pharmacological action, are excellent in safety and can solve the problem described above, thus completing the present invention. Accordingly, the object of the present invention is to provide a clinically highly useful, novel pharmaceutical preparation having good balance between effects and side effects thereby solving the drawbacks of conventional agents such as an agent for treatment of acute nerve degeneration diseases after cerebral ischemia and cerebrospinal injuries, an agent for treatment of chronic nerve degeneration disease, anti-epileptic agent, an analgesic, a muscle relaxant, or an agent for treatment of demyelinating disease.
That is, the first aspect of the present invention relates to:
1) a heterodiazinon compound represented by the formula: 
(wherein A represents oxygen, sulfur or a group represented by the formula  greater than NR3 (wherein R3 represents hydrogen atom or a lower alkyl group); R1 and R2 are the same as or different from each other and each represents an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl alkyl group, an optionally substituted aryl alkenyl group, an optionally substituted heteroaryl alkenyl group, an optionally substituted piperidyl group, an optionally substituted piperazinyl group, a morpholinyl group, an optionally substituted lower cycloalkyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, an adamantyl group, an optionally substituted amino group or an optionally substituted amide group; and R4 and R5 are the same as or different from each other and each represents hydrogen atom, hydroxyl group, a halogen atom, nitrile group, nitro group, a lower alkyl group, an aryl group or a heteroaryl group), a pharmacologically acceptable salt thereof or hydrates thereof,
provided that the compounds represented by the following formula (II): 
(wherein R11 and R12 are the same as or different from each other and each represents hydrogen atom, fluorine, chlorine, bromine, iodine, a C1-C2 fluoroalkyl group, a C1-C2 chloroalkyl group, a C1-C2 bromoalkyl group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C7-C9 aralkyl group, phenyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a C1-C6 alkylsulfinyl group, a C7-C9 aralkoxy group, phenoxy group, phenylthio group, phenylsulfonyl group, an alkali metal carboxylate C2-C5 alkoxycarbonyl group or a group represented by the formula xe2x80x94N(R15)R16 (wherein R15 and R16 are the same as or different from each other and each represents hydrogen atom or a C1-C2 alkyl group); and R13 and R14 are the same as or different from each other and each represents a C1-4 alkylsulfonyl group, nitro group, a group represented by the formula xe2x80x94OCHnX3xe2x88x92n (wherein X represents fluorine, chlorine, bromine or iodine; and n is an integer of 1 to 3) or the same groups as defined above for R11 and R12) are excluded;
2) the heterodiazinon compound according to 1), a pharmacologically acceptable salt thereof or hydrates thereof, wherein R4 and R5 are the same as or different from each other and each represents hydrogen atom, hydroxyl group, a C1-6 alkyl group or an aryl group;
3) the heterodiazinon compound according to 1), a pharmacologically acceptable salt thereof or hydrates thereof, wherein R4 is hydrogen atom and R5 is hydroxyl group, a C1-6 alkyl group or an aryl group;
4) the heterodiazinon compound according to 1), a pharmacologically acceptable salt thereof or hydrates thereof, wherein R4 is hydrogen atom and R5 is hydroxyl group, methyl group, ethyl group, n-propyl group, i-propyl group or phenyl group;
5) the heterodiazinon compound according to 1), a pharmacologically acceptable salt thereof or hydrates thereof, wherein R4 and R5 are the same as or different from each other and each represents methyl group, ethyl group, n-propyl group or i-propyl group; and
6) the heterodiazinon compound according to 1), a pharmacologically acceptable salt thereof or hydrates thereof, wherein A is oxygen.
The above heterodiazinon compound (I) wherein R4 and R5 are hydrogen atoms is the same as the following heterodiazinon compound (III).
Further, the second aspect of the present invention relates to:
7) a heterodiazinon compound (III) represented by the following formula: 
(wherein A represents oxygen, sulfur or a group represented by the formula  greater than NR3 (wherein R3 represents hydrogen atom or a lower alkyl group); and R1 and R2 are the same as or different from each other and each represents an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl alkyl group, an optionally substituted aryl alkenyl group, an optionally substituted heteroaryl alkenyl group, an optionally substituted piperidyl group, an optionally substituted piperazinyl group, a morpholinyl group, an optionally substituted lower cycloalkyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, an adamantyl group, an optionally substituted amino group or an optionally substituted amide group), a pharmacologically acceptable salt thereof or hydrates thereof, provided that the heterodiazinon compounds represented by the formula (II): 
(wherein R11 and R12 are the same as or different from each other and each represents hydrogen atom, fluorine, chlorine, bromine, iodine, a C1-C2 fluoroalkyl group, a C1-C2 chloroalkyl group, a C1-C2 bromoalkyl group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C7-C9 aralkyl group, phenyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a C1-C6 alkylsulfinyl group, a C7-C9 aralkoxy group, phenoxy group, phenylthio group, phenylsulfonyl group, an alkali metal carboxylate C2-C5 alkoxycarbonyl group or a group represented by the formula xe2x80x94N(R15)R16 (wherein R15 and R16 are the same as or different from each other and each represents hydrogen atom or a C1-C2 alkyl group); and R13 and R14 are the same as or different from each other and each represents a C1-4 alkylsulfonyl group, nitro group, a group represented by the formula xe2x80x94OCHnX3xe2x88x92n (wherein X represents fluorine, chlorine, bromine or iodine; and n is an integer of 1 to 3) or the same groups as defined above for R11 and R12) are excluded;
8) the heterodiazinon compound according to 7), a pharmacologically acceptable salt thereof or hydrates thereof, wherein R1 is an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl alkyl group, an optionally substituted aryl alkenyl group, an optionally substituted heteroaryl alkenyl group, a morpholinyl group, a lower cycloalkyl group, an optionally substituted amino group or an optically substituted amide group; and R2 is an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl alkyl group, a lower cycloalkyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, an optionally substituted piperidyl group or an adamantyl group;
9) the heterodiazinon compound according to 7) or 8), a pharmacologically acceptable salt thereof or hydrates thereof, wherein the substituent groups on R1 and R2 are hydrogen atom, in halogen atom, hydroxyl group, lower alkyl group, lower alkenyl group, lower alkynyl group, lower alkoxy group, lower thioalkoxy group, hydroxy lower thioalkoxy group, arylthio group, heteroaryl thio group, heteroaryl(hydroxy)alkyl group, halogenated lower alkyl group, hydroxy lower alkyl group, dihydroxy lower alkyl group, halogenated(hydroxy)lower alkyl group, hydroxyalkenyl group, hydroxyalkynyl group, hydroxy lower cycloalkenyl group, lower alkoxy(hydroxy)alkyl group, lower alkoxy(hydroxy)alkoxy group, lower alkoxy alkyl group, lower alkoxy alkoxy group, lower thioalkoxy alkoxy group, lower alkyl sulfonyl alkoxy group, hydroxy lower alkoxy group, dihydroxy lower alkoxy group, hydroxy lower alkyl alkoxy group, hydroxy imino lower alkyl group, lower cycloalkyl(hydroxy)alkyl group, aralkyl group, hydroxyaralkyl group, cyano group, cyano lower alkyl group, amide group, N-lower alkyl amide group, N-lower cycloalkyl amide group, N,N-di-lower alkyl amide group, N-hydroxy lower alkyl amide group, N-hydroxy lower alkyl-N-lower alkyl amide group, N-aryl amide group, cyclic aminocarbonyl group, carbamoyl group, N-lower alkyl carbamoyl group, N,N-di-lower alkyl carbamoyl group, aminosulfonyl group, cyclic aminosulfonyl group, N-lower alkyl aminosulfonyl group, N-lower cycloalkyl aminosulfonyl group, N,N-di-lower alkyl aminosulfonyl group, N-hydroxy lower alkyl aminosulfonyl group, N-lower alkoxyalkyl aminosulfonyl group, N-halogenated lower alkyl sulfonyl group, pyrrolidinyl sulfonyl group, lower alkyl sulfonyl amino alkyl group, N-lower alkyl aminosulfonyl alkyl group, N,N-di-lower alkyl aminosulfonyl alkyl group, lower acyl group, lower acyl alkyl group, lower cycloalkyl(hydroxy)methyl group, tetrahydropyranyl group, hydroxytetrahydropyranyl group. hydroxy lower alkyl tetrahydropyranyl group, lower acyl amino alkyl group, (thiazole-2-yl) hydroxymethyl group, di(thiazole-2-yl) hydroxymethyl group, lower alkyl sulfonyl group, lower alkoxy alkyl sulfonyl group, hydroxy lower alkyl sulfonyl group, lower alkyl sulfonyl alkyl group, N-lower alkyl amide alkyl group, aryl group, aralkyl group, heteroaryl group, heteroaryl lower alkyl group, heteroaryl lower alkoxy group, heteroaryl sulfonyl group, 4-morpholinyl sulfonyl group, 4-oxythiomorpholinyl sulfonyl group, 4-dioxythiomorpholinyl sulfonyl group, 4-morpholinyl sulfonyl group, hydroxy lower cycloalkyl group, hydroxy lower cycloalkyloxy group, hydroxy cycloalkenyl group, halogenated hydroxy lower alkyl group, 4-hydroxypiperidyl group, 4-lower alkoxypiperidyl group, xcfx89,xcfx89-lower alkylene dioxyalkyl group, xcfx89,xcfx89-lower alkylene dioxy alkoxy group, lower cycloalkyl hydroxy methyl group, aryloxy group, aryl aminosulfonyl group, amino group, lower alkyl amino group, di-lower alkyl amino group, hydroxy lower alkyl amino group, lower acyl amino group, hydroxy lower acyl amino group, lower alkyl sulfonyl amino group, pyridyl lower alkoxy group, lower alkyl pyridyl alkoxy group, lower alkoxy hydroxy alkoxy group, lower thioalkoxy alkoxy group, lower alkyl sulfonyl alkoxy group, N-lower alkyl carbamoyl group, N,N-di-lower alkyl carbamoyl group, N-hydroxy lower alkyl carbamoyl group, N-hydroxy lower alkyl-N-lower alkyl carbamoyl group, halogenated lower alkoxy group, cyano lower alkoxy group, hydroxy lower cycloalkoxy group, trifluoromethyl group, trifluoromethoxy group, amino lower alkoxy group, N-lower alkyl aminoalkoxy group, N,N-di-lower alkyl aminoalkoxy group, lower acyl alkoxy group, lower acyl aminoalkoxy group, (1,3-dioxolanyl)lower alkyl group, (1,3-dioxolanyl)lower alkoxy group, amide lower alkoxy group, 4-(hydroxyalkyl)tetrahydropyran-4-yl group, 2,3-dihydrobenzofuranyl group, 2-hydroxy-2-alkyl-2,3-dihydrobenzofuranyl group, indanonyl group, hydroxyindanyl group, imidazolyl lower alkoxy group, succimide group or 2-oxazolidone-3-yl group, optionally substituted benzoyloxy lower alkyl group, optionally substituted amino lower alkyl group, optionally substituted amino lower alkoxy group, optionally substituted aralkyloxy group, optionally substituted heteroaryl alkoxy group, optionally substituted morpholinyl lower alkoxy group, optionally substituted piperidyl lower alkoxy group, optionally substituted piperazinyl lower alkoxy group or optionally substituted pyrrolidinyl lower alkoxy group;
10) the heterodiazinon derivative according to 7) to 9), a pharmacologically acceptable salt thereof or hydrates thereof, which are represented by the following formula: 
wherein R1 and R2 have the same meanings as defined above;
11) the heterodiazinon compound according to 7) to 10), a pharmacologically acceptable salt thereof or hydrates thereof, wherein the aryl group is a group selected from phenyl group, indenyl group, naphthyl group, azulenyl group, heptalenyl group and anthnyl group; the heteroaryl group is a group selected form thienyl group, furyl group, pyranyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, isothiazolyl group, thiazolyl group, thiadiazolyl group, isoxazolyl group, pyridyl group, pyrazinyl group, pyrimidyl group, pyridazinyl group, indolizinyl group, isoindolyl group, indolyl group, indazolyl group, isoquinolyl group, quinolyl group, phthalazinyl group, naphthylidinyl group, quinoxalinyl group, quinazolinyl group and cinolynyl group; and the lower cycloalkyl group is a group selected from cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and cycloctyl group; and
12) the heterodiazinon compound according to 7) to 11), which is a compound selected from the following compounds or pharmacologically acceptable salts thereof or hydrates thereof.
(1) 2-(2-Pyridyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(2) 2-(2-pyrazinyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(3) 2-(1-methyl-2-pyrolyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(4) 2,4-diphenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(5) 2-(2,3-dimethoxyphenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(6) 2-(2-pyrrolyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(7) 2-(2-quinolyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(8) 2-(6-methyl-2-pyridyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(9) 2-benzoyloxymethyl-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(10) 2-(2-pyridyl)-4-(2,4-difluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(11) 2-(2-pyridyl)-4-cyclohexyl-4H-1,3,4-oxadiazine-5(6H)-one,
(12) 2-(2-chloro-4-pyridyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(13) 2-(3-methoxy-2-pyridyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(14) 2-(3-hydroxy-2-pyridyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(15) 2-styryl-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(16) 2-[2-(3-pyridyl)vinyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(17) 2-(2-methoxyphenyl)-4-(2-bromophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(18) 2-(4-nitrophenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(19) 2-(3-nitrophenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(20) 2-(2-nitrophenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(21) 2-(4-morpholinyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(22) 2-cyclohexyl-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(23) 2-dimethylamino-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(24) 2-dimethylamino-4-phenyl-4H-1,3,4-thiadiazine-5(6H)-one,
(25) 2-(2,6-dimethoxyphenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(26) 2-(2-methoxyphenyl)-4-(2-fluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(27) 2-phenyl-4-cyclohexyl-4H-1,3,4-oxadiazine-5(6H)-one,
(28) 2-(2-methoxyphenyl)-4-cyclohexyl-4H-1,3,4-oxadiazine-5(6H)-one,
(29) 2-(3-pyridyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(30) 2-phenyl-4-(2-bromophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(31) 2-(2-thienyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(32) 2-benzyl-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(33) 2-(2-pyridyl)-4-(2-bromophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(34) 2-(2-pyridyl)-4-(2-fluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(35) 2-(2-pyridyl)-4-(2-methoxyphenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(36) 2-phenyl-4-(2-cyanoeyphenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(37) 2-phenyl-4-(2-nitrophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(38) 2-phenyl-4-(2-pyridyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(39) 2-phenyl-4-(3-pyridyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(40) 2-phenyl-4-(3-cyano-2-pyridyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(41) 2-phenyl-4-(2-hydroxymethylphenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(42) 2-phenyl-4-(2-cyano-3-pyridyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(43) 2-phenyl-4-(2-thienyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(44) 2-phenyl-4-(3-thienyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(45) 2-phenyl-4-(4-cyanophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(46) 2-phenyl-4-(3-cyanophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(47) 2-phenyl-4-(2-cyano-3-thienyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(48) 2-(2-hydroxyphenyl)-4-(2-bromophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(49) 2-(2-hydroxyphenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(50) 2-phenyl-4-(2-hydroxyphenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(51) 2-(2-hydroxyphenyl)-4-(2-fluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(52) 2-(2-hydroxyphenyl)-4-(4-fluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(53) 2-(2-hydroxyphenyl)-4-(2,4-difluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(54) 2-[2-(2-dimethylamino)ethoxyphenyl]-4-(2-bromophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(55) 2-[2-(4-pyridyl)methoxyphenyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(56) 2-{2-[2-(4-morpholinyl)ethoxy]phenyl}-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(57) 2-[2-(2-pyridyl)methoxyphenyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(58) 2-[2-(3-pyridyl)methoxyphenyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(59) 2-{2-[2-(1-piperidyl)ethoxy]phenyl}-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(60) 2-{2-[2-(1-pyrrolidinyl)ethoxy]phenyl}-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(61) 2-[2-(2-dimethylaminoethoxy)phenyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(62) 2-[2-(3-dimethylaminopropoxy)phenyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(63) 2-{2-[3-(1-piperidinyl)propoxy]phenyl}-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(64) 2-phenyl-{4-[2-(4-morpholinyl)ethoxy]phenyl}-4H-1,3,4-oxadiazine-5(6H)-one,
(65) 2-phenyl-4-[2-(2-dimethylaminoethoxy)phenyl]-4H-1,3,4-oxadiazine-5(6H)-one,
(66) 2-[2-(2-dimethylaminoethoxy)phenyl]-4-(2-fluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(67) 2-{2-[2-(4-morpholinyl)ethoxy]phenyl}-4-(2-fluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(68) 2-{2-[2-(4-morpholinyl)ethoxy]phenyl}-4-(2-bromophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(69) 2-{2-[2-(4-morpholinyl)ethoxy]phenyl}-4-cyclohexyl-4H-1,3,4-oxadiazine-5(6H)-one,
(70) 2-{2-[2-(4-morpholinyl)ethoxy]phenyl}-4-(4-fluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(71) 2-{2-[2-(4-morpholinyl)ethoxy]phenyl}-4-(2,4-difluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(72) 2-[3-(2-hydroxyethoxy)-2-pyridyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(73) 2-{3-[2-(4-morpholinyl)ethoxy]-2-pyridyl}-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(74) 2-{3-[2-(1-piperidyl)ethoxy]-2-pyridyl}-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(75) 2-{3-[2-(1-pyrrolidinyl)ethoxy]-2-pyridyl}-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(76) 2-{3-[2-(1-methyl-2-pyrrolidinyl)ethoxy]-2-pyridyl}-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(77) 2-[3-(2-dimethylaminoethoxy)-2-pyridyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(78) 2-(3-aminophenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(79) 2-(2-aminophenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(80) 2-phenyl-4-(tetrahydro-4H-pyran-4-yl)-4H-1,3,4-oxadiazine-5(6H)-one,
(81) 2-phenyl-4-(1-methyl-4-piperidyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(82) 2-phenyl-4-(3-quinuclidinyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(83) 2-pyridyl-4-(1-benzyl-4-piperidyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(84) 2-phenyl-4-(3-tetrahydrofuranyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(85) 2-phenyl-4-cyclopentyl-4H-1,3,4-oxadiazine-5(6H)-one,
(86) 2-phenyl-4-(1-benzyl-4-piperidyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(87) 2-phenyl-4-[1-(2-pyridyl)ethyl]-4H-1,3,4-oxadiazine-5(6H)-one,
(88) 2-phenyl-4-[1-(3-pyridyl)ethyl]-4H-1,3,4-oxadiazine-5(6H)-one,
(89) 2-phenyl-4-[1-(4-pyridyl)ethyl]-4H-1,3,4-oxadiazine-5(6H)-one,
(90) 2-(3-dimethylaminophenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(91) 2-(2-dimethylaminophenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(92) 2-[2-(4-pyridyl)methylaminophenyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(93) 2-[2-(3-pyridyl)methylaminophenyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(94) 2-(4-pyridyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(95) N-(2-pyridyl)-[4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one-2-yl]carboxamide,
(96) N-(3-pyridyl)-[4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one-2-yl]carboxamide,
(97) N-(4-pyridyl)-[4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one-2-yl]carboxamide,
(98) 1,3-diphenyl-4-methyl-4,5-dihydro-1,2,4-triazine-6(1H)-one and
(99) 1-phenyl-3-(2-pyridyl)-4-methyl-4,5-dihydro-1,2,4-triazine-6(1H)-one.
Further, the third aspect of the present invention relates to:
13) a pharmaceutical preparation comprising a heterodiazinon compound represented by the formula: 
(wherein A represents oxygen, sulfur or a group represented by the formula  greater than NR3 (wherein R3 represents hydrogen atom or a lower alkyl group); R1 and R2 are the same as or different from each other and each represents an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl alkyl group, an optionally substituted aryl alkenyl group, an optionally substituted heteroaryl alkenyl group, an optionally substituted piperidyl group, an optionally substituted piperazinyl group, a morpholinyl group, an optionally substituted lower cycloalkyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, an adamantyl group, an optionally substituted amino group or an optionally substituted amide group; and R4 and R5 are the same as or different from each other and each represents hydrogen atom, hydroxyl group, a halogen atom, nitrile group, nitro group, a lower alkyl group, an aryl group or a heteroaryl group), a pharmaceutically acceptable salt thereof or hydrates thereof;
14) a pharmaceutical preparation comprising a heterodiazinon compound represented by the following formula: 
(wherein A represents oxygen, sulfur or a group represented by the formula  greater than NR3 (wherein R3 represents hydrogen atom or a lower alkyl group); and R1 and R2 are the same as or different from each other and each represents an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl alkyl group, an optionally substituted aryl alkcenyl group, an optionally substituted heteroaryl alkenyl group, an optionally substituted piperidyl group, an optionally substituted piperazinyl group, a morpholinyl group, an optionally substituted lower cycloalkyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, an adamantyl group, an optionally substituted amino group or an optionally substituted amide group), or a pharmaceutically acceptable salt thereof or hydrates thereof;
15) the pharmaceutical preparation according to 13) or 14) for use as an agent for preventing, treating and ameliorating diseases against which non-N-methyl-D-aspartate excitatory amino acid receptor antagonistic action is effective;
16) the pharmaceutical preparation according to 13) or 14) for use as an agent for preventing, treating and ameliorating diseases against which 2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonistic action is effective;
17) the pharmaceutical preparation according to 13) or 14) for use as an agent for preventing, treating and ameliorating nerve degeneration diseases;
18) the pharmaceutical preparation according to 13) or 14) for use as an agent for preventing, treating and ameliorating demyelinating nerve diseases;
19) the pharmaceutical preparation according to 13) or 14) for use as an agent for preventing, treating and ameliorating acute nerve degeneration after cerebral ischemia, traumas in the head and spinal injuries, Alzheimer""s disease, Parkinson""s disease, amyotrophic lateral sclerosis, Huntington""s chorea, epilepsy, pain, multiple sclerosis, encephalomyelitis, Guillain Barre syndrome, Marchiafava Bignami disease, Devic disease, Balo disease, HIV or HTLV myelopathy or leukoencephalopathy; and
20) the heterodiazinon compound of the present invention which as a compound having non-NMDA excitatory amino acid receptor antagonistic action, particularly AMPA receptor antagonistic action, is used as an agent for preventing, treating and ameliorating nerve degeneration diseases, specifically 1) disturbance such as motor disturbance, hindrance of sensibility and abnormal behavior, caused by disturbance after cerebral ischemia and acute nerve degeneration after cerebrospinal injuries; 2) chronic nerve degeneration diseases such as Alzheimer""s disease, Parkinson""s disease, amyotrophic lateral sclerosis and Huntington""s chorea; 3) epilepsy; 4) chronic pain, migraine, cancerous pain, and pain originating in diabetic nerve disturbance; 5) spastic paralysis or 6) demyelinating diseases such as multiple sclerosis, encephalomyelitis, Guillain Barre syndrome, Marchiafava Bignami disease, Devic disease, Balo disease, REFSAME disease, TANGIEL disease, DEJERIN-SOTAS disease, HIV or HTLV myelopathy, and leukoencephalopathy.
That is, the present invention relates to a method of preventing, treating and ameliorating diseases against which non-N-methyl-D-aspartate excitatory amino acid receptor antagonistic action is effective; a method of preventing, treating and ameliorating diseases against which 2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonistic action is effective; a method of preventing, treating and ameliorating nerve degeneration diseases; and a method of preventing, treating and ameliorating acute nerve degeneration after cerebral ischemia, traumas in the head and spinal injuries, Alzheimer""s disease, Parkinson""s disease, amyotrophic lateral sclerosis, Huntington""s chorea, epilepsy, pain, multiple sclerosis, encephalomyelitis, Guillain Barre syndrome, Marchiafava Bignami disease, Devic disease, Balo disease, HIV or HTLV myelopathy, or leukoencephalopathy, which comprises administering a pharmacologically effective amount of the pharmaceutical preparation to a patient. Further, it relates to use thereof for producing the above-mentioned pharmaceutical preparation and a pharmaceutical composition comprising it.
Further, the present invention provides use of the compound represented by the formula (II) above, a pharmacologically acceptable salt thereof or hydrates thereof as a pharmaceutical preparation, and the details are the same as of Compound (I). That is, the present invention provides a pharmaceutical preparation comprising Compound (II) etc., a therapeutic method which comprising administrating the compound, and use thereof for producing a pharmaceutical preparation.
Hereinafter, the meanings of symbols, terms etc. used in the present specification are described, and the present invention is described in detail.
In the specification, the structural formulae of the compounds may, for convenience"" sake, indicate a certain isomer, but the present invention encompasses every possible isomer such as geometric isomer, optical isomer based on asymmetric carbon, stereoisomer and tautomer, which can occur in the structures of the compounds, as well as mixtures of such isomers. Accordingly, the compounds of the present specification are not limited by the formulae shown for convenience"" sake, and may be a certain isomer or a mixture thereof. Further, the compounds of the present invention encompass those in any crystalline polymorphism without limitation, and they may be crystals in single crystal form or a mixture thereof, or anhydrates thereof or hydrates thereof.
The heterodiazinon compound of the present invention, a pharmacologically acceptable salt thereof or hydrates thereof are represented by the following formula: 
wherein A represents oxygen, sulfur or a group represented by the formula  greater than NR3 (wherein R3 represents hydrogen atom or a lower alkyl group); R1 and R2 are the same as or different from each other and each represents an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl alkyl group, an optionally substituted aryl alkenyl group, an optionally substituted heteroaryl alkenyl group, an optionally substituted piperidyl group, an optionally substituted piperazinyl group, a morpholinyl group, an optionally substituted lower cycloalkyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, an adamantyl group, an optionally substituted amino group or an optionally substituted amide group; and R4 and R5 are the same as or different from each other and each represents hydrogen atom, hydroxyl group, a halogen atom, nitrile group, nitro group, a lower alkyl group, an aryl group or a heteroaryl group,
provided that the compound disclosed in U.S. Pat. No. 4,670,555 (U.S. Pat. No. 4,782,066), represented by the following formula (II) is excluded. 
In the formula, R11 and R12 are the same as or different from each other and each represents hydrogen atom, fluorine, chlorine, bromine, iodine, a C1-C2 fluoroalkyl group, a C1-C2 chloroalkyl group, a C1-C2 bromoalkyl group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C7-C9 aralkyl group, phenyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a C1-C6 alkylsulfinyl group, a C7-C9 aralkoxy group, phenoxy group, phenylthio group, phenylsulfonyl group, an alkali metal carboxylate C2-C5 alkoxycarbonyl group or a group represented by the formula xe2x80x94N(R15)R16 (wherein R15 and R16 are the same as or different from each other and each represents hydrogen atom or a C1-C2 alkyl group); and R13 and R14 are the same as or different from each other and each represents a C1-4 alkylsulfonyl group, nitro group, a group represented by the formula xe2x80x94OCHnX3xe2x88x92n (wherein X represents fluorine, chlorine, bromine or iodine; and n is an integer of 1 to 3) or the same groups as defined above for R11 and R12.
The compounds disclosed in the above-mentioned U.S. Pat. No. 4,670,555 (U.S. Pat. No. 4,782,066) are concerned with a nematocidal agent or a miticidal agent, and are completely different in chemical structure and pharmacological action from the heterodiazinon compounds of the present invention.
In the definition of the present invention, the lower alkyl group refers to C1-6 alkyl groups, for example straight-chain or branched alkyl groups such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, n-pentyl group, i-pentyl group, neopentyl group, hexyl group, 1-methyl propyl group, 1-methyl butyl group and 2-methyl butyl group.
The lower alkoxy group refers to a group having the above lower alkyl group bound to oxygen, and include e.g. straight-chain or branched alkoxy groups such as methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, t-butoxy group, pentyloxy group and hexyloxy group.
The halogen atom refers""specifically to fluorine, chlorine, bromine or iodine.
The aryl group refers to a hydrocarbon group that has formed an aromatic ring, and includes e.g. a phenyl group, indenyl group, naphthyl group, azulenyl group, heptalenyl group, anthnyl group etc., which may further be substituted. Among these groups, a phenyl group is more preferable.
The heteroaryl group refers to a group that has been formed from carbon atoms and hydrogen atoms together with one or more nitrogen atoms, oxygen atoms or sulfur atoms, and examples thereof include thienyl group, furyl group, pyranyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, isothiazolyl group, thiazolyl group, thiadiazolyl group, isoxazolyl group, pyridyl group, pyrazinyl group, pyrimidyl group, pyridazinyl group, indolizinyl group, isoindolyl group, indolyl group, indazolyl group, isoquinolyl group, quinolyl group, phthalazinyl group, naphthylidinyl group, quinoxalinyl group, quinazolinyl group and cinolynyl group, and these groups maybe further substituted. Among these groups, a pyridyl group, pyrazinyl group, pyrrolyl group, quinolyl group and thienyl group are more preferable.
The lower cycloalkyl group refers to C3-8 cyclic hydrocarbon groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and cycloctyl group. Among these groups, a cyclohexyl group is more preferable.
The optionally substituted amino group or the optionally substituted amide group refers to groups of the formula xe2x80x94NH, or xe2x80x94CONH2, or to groups of the formula wherein one or two hydrogen atoms on the nitrogen atom have been replaced. Although the type of the substituent group is not limited, a lower alkyl group can be specifically mentioned.
The substituent groups on R1 and R2 include hydrogen atom, halogen atom, hydroxyl group, lower alkyl group, lower alkenyl group, lower alkynyl group, lower alkoxy group, lower thioalkoxy group, hydroxy lower thioalkoxy group, arylthio group, heteroaryl thio group, heteroaryl(hydroxy)alkyl group, halogenated lower alkyl group, hydroxy lower alkyl group, dihydroxy lower alkyl group, halogenated(hydroxy)lower alkyl group, hydroxyalkenyl group, hydroxyalkynyl group, hydroxy lower cycloalkenyl group, lower alkoxy(hydroxy)alkyl group, lower alkoxy(hydroxy)alkoxy group, lower alkoxy alkyl group, lower alkoxy alkoxy group, lower thioalkoxy alkoxy group, lower alkyl sulfonyl alkoxy group, hydroxy lower alkoxy group, dihydroxy lower alkoxy group, hydroxy lower alkyl alkoxy group, hydroxy imino lower alkyl group, lower cycloalkyl(hydroxy)alkyl group, aralkyl group, hydroxyaralkyl group, cyano group, cyano lower alkyl group, amide group, N-lower alkyl amide group, N-lower cycloalkyl amide group, N,N-di-lower alkyl amide group, N-hydroxy lower alkyl amide group, N-hydroxy lower alkyl-N-lower alkyl amide group, N-aryl amide group, cyclic aminocarbonyl group, carbamoyl group, N-lower alkyl carbamoyl group, N,N-di-lower alkyl carbamoyl group, aminosulfonyl group, cyclic aminosulfonyl group, N-lower alkyl aminosulfonyl group, N-lower cycloalkyl aminosulfonyl group, N,N-di-lower alkyl aminosulfonyl group, N-hydroxy lower alkyl aminosulfonyl group, N-lower alkoxy alkyl aminosulfonyl group, N-halogenated lower alkyl sulfonyl group, pyrrolidinyl sulfonyl group, lower alkyl sulfonyl amino alkyl group, N-lower alkyl aminosulfonyl alkyl group, N,N-di-lower alkyl aminosulfonyl alkyl group, lower acyl group, lower acyl alkyl group, lower cycloalkyl(hydroxy)methyl group, tetrahydropyranyl group, hydroxytetrahydropyranyl group, hydroxy lower alkyl tetrahydropyranyl group, lower acyl amino alkyl group, (thiazole-2-yl)hydroxymethyl group, di(thiazole-2-yl)hydroxymethyl group, lower alkyl sulfonyl group, lower alkoxy alkyl sulfonyl group, hydroxy lower alkyl sulfonyl group, lower alkyl sulfonyl alkyl group, N-lower alkyl amide alkyl group, aryl group, aralkyl group, heteroaryl group, heteroaryl lower alkyl group, heteroaryl lower alkoxy group, heteroaryl sulfonyl group, 4-morpholinyl sulfonyl group, 4-oxythiomorpholinyl sulfonyl group, 4-dioxythiomorpholinyl sulfonyl group, 4-morpholinyl sulfonyl group, hydroxy lower cycloalkyl group, hydroxy lower cycloalkyloxy group, hydroxy cycloalkenyl group, halogenated hydroxy lower alkyl group, 4-hydroxypiperidyl group, 4-lower alkoxypiperidyl group, xcfx89,xcfx89-lower alkylene dioxyalkyl group, xcfx89,xcfx89-lower alkylene dioxy alkoxy group, lower cycloalkyl hydroxy methyl group, aryloxy group, aryl aminosulfonyl group, amino group, lower alkyl amino group, di-lower alkyl amino group, hydroxy lower alkyl amino group, lower acyl amino group, hydroxy lower acyl amino group, lower alkyl sulfonyl amino group, pyridyl lower alkoxy group, lower alkyl pyridyl alkoxy group, lower alkoxy hydroxy alkoxy group, lower thioalkoxy alkoxy group, lower alkyl sulfonyl alkoxy group, N-lower alkyl carbamoyl group, N,N-di-lower alkyl carbamoyl group, N-hydroxy lower alkyl carbamoyl group, N-hydroxy lower alkyl-N-lower alkyl carbamoyl group, halogenated lower alkoxy group, cyano lower alkoxy group, hydroxy lower cycloalkoxy group, trifluoromethyl group, trifluoromethoxy group, amino lower alkoxy group, N-lower alkyl aminoalkoxy group, N,N-di-lower alkyl aminoalkoxy group, lower acyl alkoxy group, lower acyl aminoalkoxy group, (1,3-dioxolanyl) lower alkyl group, (1,3-dioxolanyl) lower alkoxy group, amide lower alkoxy group, 4-(hydroxy alkyl) tetrahydropyran-4-yl group, 2,3-dihydrobenzofuranyl group, 2-hydroxy-2-alkyl-2,3-dihydrobenzofuranyl group, indanonyl group, hydroxyindanyl group, imidazolyl lower alkoxy group, succimide group or 2-oxazolidone-3-yl group, optionally substituted benzoyloxy lower alkyl group, optionally substituted amino lower alkyl group, optionally substituted amino lower alkoxy group, optionally substituted aralkyloxy group, optionally substituted heteroaryl alkoxy group, optionally substituted morpholinyl lower alkoxy group, optionally substituted piperidyl lower alkoxy group, optionally substituted piperazinyl lower alkoxy group and optionally substituted pyrrolidinyl lower alkoxy group.
Among those enumerated above, more preferable groups include a hydroxyl group, halogen atom, optionally substituted amino group, lower alkyl group, lower alkoxy group, nitro group, cyano group, hydroxy lower alkyl group, optionally substituted benzoyloxy lower alkyl group, optionally substituted amino lower alkyl group, optionally substituted amino lower alkoxy group, optionally substituted aralkyloxy group, optionally substituted heteroaryl alkoxy group, optionally substituted morpholinyl lower alkoxy group, optionally substituted piperidyl lower alkoxy group, optionally substituted piperazinyl lower alkoxy group, optionally substituted pyrrolidinyl lower alkoxy group, and hydroxy lower alkoxy group.
In the formula (I) above, R4 and R5 are the same as or different from each other and each preferably represents hydrogen atom, hydroxyl group, a C1-6 alkyl group or an aryl group; more preferably R4 represents hydrogen atom while R5 represents hydrogen atom, hydroxyl group, a C1-6 alkyl group or an aryl group; further preferably R4 represents hydrogen atom while R5 represents hydrogen atom, hydroxyl group, methyl group, ethyl group, n-propyl group, i-propyl group or phenyl group; and most preferably R4 and R5 are the same as or different from each other and each represents hydrogen atom, methyl group, ethyl group, n-propyl group or i-propyl group.
In the case of the above formula (I) wherein R4 and R5 are hydrogen atoms, the heterodiazinon compounds (III) are represented by the following formula: 
wherein A represents oxygen, sulfur or a group represented by the formula  greater than NR3 (wherein R3 represents hydrogen atom or a lower alkyl group) and R1 and R2 are the same as or different from each other and each represents an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl alkyl group, an optionally substituted aryl alkenyl group, an optionally substituted heteroaryl alkenyl group, an optionally substituted piperidyl group, an optionally substituted piperazinyl group, a morpholinyl group, an optionally substituted lower cycloalkyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, an adamantyl group, an optionally substituted amino group or an optionally substituted amide group.
However, the compounds disclosed in U.S. Pat. No. 4,670,555 (U.S. Pat. No. 4,782,066), represented by the following formula (II): 
(wherein R11 and R12 are the same as or different from each other and each represents hydrogen atom, fluorine, chlorine, bromine, iodine, a C1-C2 fluoroalkyl group, a C1-C2 chloroalkyl group, a C1-C2 bromoalkyl group, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C7-C9 aralkyl group, phenyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a C1-C6 alkylsulfinyl group, a C7-C9 aralkoxy group, phenoxy group, phenylthio group, phenylsulfonyl group, an alkali metal carboxylate C2-C5 alkoxycarbonyl group or a group represented by the formula xe2x80x94N(15)R16 (wherein R15 and R16 are the same as or different from each other and each represents hydrogen atom or a C1-C2 alkyl group); and R13 and R14 are the same as or different from each other and each represents a C1-4 alkylsulfonyl group, nitro group, a group represented by the formula xe2x80x94OCHnX3-n (wherein X represents fluorine, chlorine, bromine or iodine; and n is an integer of 1 to 3) or the same groups as defined above for R11 and R12) are excluded.
In the above definition, the xe2x80x9clower alkyl groupxe2x80x9d, xe2x80x9clower alkoxy groupxe2x80x9d, xe2x80x9chalogen atomxe2x80x9d, xe2x80x9caryl groupxe2x80x9d, xe2x80x9cheteroaryl groupxe2x80x9d, xe2x80x9clower cycloalkyl groupxe2x80x9d, xe2x80x9coptionally substituted amino groupxe2x80x9d, xe2x80x9coptionally substituted amide groupxe2x80x9d and xe2x80x9csubstituent groups on R1 and/or R2xe2x80x9d have the same meanings as defined above. Preferable among those enumerated above are hydroxyl group, halogen atom, optionally substituted amino group, lower alkyl group, lower alkoxy group, nitro group, cyano group, hydroxy lower alkyl group, optionally substituted benzoyloxy lower alkyl group, optionally substituted amino lower alkyl group, optionally substituted amino lower alkoxy group, optionally substituted aralkyloxy group, optionally substituted heteroaryl alkoxy group, optionally substituted morpholinyl lower alkoxy group, optionally substituted piperidyl lower alkoxy group, optionally substituted piperazinyl lower alkoxy group, optionally substituted pyrrolidinyl lower alkoxy group, and hydroxy lower alkoxy group.
The heterodiazinon compounds (III) according to the present invention include oxadiazinon compound, thiadiazine compounds and triazine compounds depending on a difference in A in the formula, preferably the oxadiazinon compounds represented by formula (IV): 
(wherein R1 and R2 have the same meanings as defined above), and the following compounds, a pharmacologically acceptable salt thereof or hydrates thereof. It goes without saying that the following compounds are not intended to limit the present invention.
(1) 2-(2-Pyridyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(2) 2-(2-pyrazinyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(3) 2-(1-methyl-2-pyrolyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(4) 2,4-diphenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(5) 2-(2,3-dimethoxyphenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(6) 2-(2-pyrrolyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(7) 2-(2-quinolyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(8) 2-(6-methyl-2-pyridyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(9) 2-benzoyloxymethyl-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(10) 2-(2-pyridyl)-4-(2,4-difluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(11) 2-(2-pyridyl)-4-cyclohexyl-4H-1,3,4-oxadiazine-5(6H)-one,
(12) 2-(2-chloro-4-pyridyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(13) 2-(3-methoxy-2-pyridyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(14) 2-(3-hydroxy-2-pyridyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(15) 2-styryl-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(16) 2-[2-(3-pyridyl)vinyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(17) 2-(2-methoxyphenyl)-4-(2-bromophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(18) 2-(4-nitrophenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(19) 2-(3-nitrophenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(20) 2-(2-nitrophenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(21) 2-(4-morpholinyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(22) 2-cyclohexyl-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(23) 2-dimethylamino-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(24) 2-dimethylamino-4-phenyl-4H-1,3,4-thiadiazine-5(6H)-one,
(25) 2-(2,6-dimethoxyphenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(26) 2-(2-methoxyphenyl)-4-(2-fluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(27) 2-phenyl-4-cyclohexyl-4H-1,3,4-oxadiazine-5(6H)-one,
(28) 2-(2-methoxyphenyl)-4-cyclohexyl-4H-1,3,4-oxadiazine-5(6H)-one,
(29) 2-(3-pyridyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(30) 2-phenyl-4-(2-bromophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(31) 2-(2-thienyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(32) 2-benzyl-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(33) 2-(2-pyridyl)-4-(2-bromophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(34) 2-(2-pyridyl)-4-(2-fluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(35) 2-(2-pyridyl)-4-(2-methoxyphenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(36) 2-phenyl-4-(2-cyanophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(37) 2-phenyl-4-(2-nitrophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(38) 2-phenyl-4-(2-pyridyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(39) 2-phenyl-4-(3-pyridyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(40) 2-phenyl-4-(3-cyano-2-pyridyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(41) 2-phenyl-4-(2-hydroxymethylphenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(42) 2-phenyl-4-(2-cyano-3-pyridyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(43) 2-phenyl-4-(2-thienyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(44) 2-phenyl-4-(3-thienyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(45) 2-phenyl-4-(4-cyanophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(46) 2-phenyl-4-(3-cyanophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(47) 2-phenyl-4-(2-cyano-3-thienyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(48) 2-(2-hydroxyphenyl)-4-(2-bromophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(49) 2-(2-hydroxyphenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(50) 2-phenyl-4-(2-hydroxyphenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(51) 2-(2-hydroxyphenyl)-4-(2-fluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(52) 2-(2-hydroxyphenyl)-4-(4-fluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(53) 2-(2-hydroxyphenyl)-4-(2,4-difluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(54) 2-[2-(2-dimethylamino)ethoxyphenyl]-4-(2-bromophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(55) 2-[2-(4-pyridyl)methoxyphenyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(56) 2-{2-[2-(4-morpholinyl)ethoxy]phenyl}-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(57) 2-[2-(2-pyridyl)methoxyphenyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(58) 2-[2-(3-pyridyl)methoxyphenyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(59) 2-{2-[2-(1-piperidyl)ethoxy]phenyl}-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(60) 2-{2-[2-(1-pyrrolidinyl)ethoxy]phenyl}-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(61) 2-[2-(2-dimethylaminoethoxy)phenyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(62) 2-[2-(3-dimethylaminopropoxy)phenyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(63) 2-{2-[3-(1-piperidinyl)propoxy]phenyl}-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(64) 2-phenyl-{4-[2-(4-morpholinyl)ethoxy]phenyl}-4H-1,3,4-oxadiazine-5(6H)-one,
(65) 2-phenyl-4-[2-(2-dimethylaminoethoxy)phenyl]-4H-1,3,4-oxadiazine-5(6H)-one,
(66) 2-[2-(2-dimethylaminoethoxy)phenyl]-4-(2-fluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(67) 2-{2-[2-(4-morpholinyl)ethoxy]phenyl}-4-(2-fluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(68) 2-{2-[2-(4-morpholinyl)ethoxy]phenyl}-4-(2-bromophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(69) 2-{2-[2-(4-morpholinyl)ethoxy]phenyl}-4-cyclohexyl-4H-1,3,4-oxadiazine-5(6H)-one,
(70) 2-{2-[2-(4-morpholinyl)ethoxy]phenyl}-4-(4-fluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(71) 2-{2-[2-(4-morpholinyl)ethoxy]phenyl}-4-(2,4-difluorophenyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(72) 2-[3-(2-hydroxyethoxy)-2-pyridyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(73) 2-{3-[2-(4-morpholinyl)ethoxy]-2-pyridyl}-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(74) 2-{3-[2-(1-piperidyl)ethoxy]-2-pyridyl}-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(75) 2-{3-[2-(1-pyrrolidinyl)ethoxy]-2-pyridyl}-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(76) 2-{3-[2-(1-methyl-2-pyrrolidinyl)ethoxy]-2-pyridyl}-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(77) 2-[3-(2-dimethylaminoethoxy)-2-pyridyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(78) 2-(3-aminophenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(79) 2-(2-aminophenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(80) 2-phenyl-4-(tetrahydro-4H-pyran-4-yl)-4H-1,3,4-oxadiazine-5(6H)-one,
(81) 2-phenyl-4-(1-methyl-4-piperidyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(82) 2-phenyl-4-(3-quinuclidinyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(83) 2-pyridyl-4-(1-benzyl-4-piperidyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(84) 2-phenyl-4-(3-tetrahydrofuranyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(85) 2-phenyl-4-cyclopentyl-4H-1,3,4-oxadiazine-5(6H)-one,
(86) 2-phenyl-4-(1-benzyl-4-piperidyl)-4H-1,3,4-oxadiazine-5(6H)-one,
(87) 2-phenyl-4-[1-(2-pyridyl)ethyl]-4H-1,3,4-oxadiazine-5(6H)-one,
(88) 2-phenyl-4-[1-(3-pyridyl)ethyl]-4H-1,3,4-oxadiazine-5(6H)-one,
(89) 2-phenyl-4-[1-(4-pyridyl)ethyl]-4H-1,3,4-oxadiazine-5(6H)-one,
(90) 2-(3-dimethylaminophenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(91) 2-(2-dimethylaminophenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(92) 2-[2-(4-pyridyl)methylaminophenyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(93) 2-[2-(3-pyridyl)methylaminophenyl]-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(94) 2-(4-pyridyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one,
(95) N-(2-pyridyl)-[4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one-2-yl]carboxamide,
(96) N-(3-pyridyl)-[4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one-2-yl]carboxamide,
(97) N-(4-pyridyl)-[4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one-2-yl]carboxamide,
(98) 1,3-diphenyl-4-methyl-4,5-dihydro-1,2,4-triazine-6(1H)-one and
(99) 1-phenyl-3-(2-pyridyl)-4-methyl-4,5-dihydro-1,2,4-triazine-6(1H)-one.
The xe2x80x9csaltxe2x80x9d and xe2x80x9cpharmacologically acceptable saltxe2x80x9d in the present invention are not limited insofar as they are salts formed with the heterodiazinon compound of the present invention, and such salts include e.g. hydrohalogenic acid salts such as hydrofluorate, hydrochloride, hydrobromate and hydroiodate; inorganic acid salts such as sulfate, nitrate, perchlorate, phosphate, carbonate and bicarbonate; organic carboxylic acid salts such as acetate, maleate, tartrate and fumarate; organic sulfonic acid salts such as methane sulfonate, trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate and camphor sulfonate; amino acid salts such as aspartate and glutamate; amine salts such as trimethylamine salt, triethylamine salt, procaine salt, pyridine salt and phenetyl benzyl amine salt; alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as magnesium salt and calcium salt, and preferable examples are hydrochloride and oxalate.
Various processes can be used for producing the compounds of the present invention, and the typical examples are as follows:
1. A Hydrazide Compound Having Substituent Groups R1 and R2 is Cyclized 
In this reaction scheme, A, R1, R2, R4 and R5 have the same meanings as defined above, X represents halogen atom, and R represents hydroxyl group or a halogen atom. In this reaction, a known hydrazine compound is reacted with a halogenated acetate compound, to give a heterodiazinon compound. Herein, the halogenated acetate compound includes e.g. chloroacetyl chloride, bromoacetyl bromide etc.
The reaction proceeds smoothly in the presence of a base. The base herein used includes potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, N,N-dimethyl aniline, etc.
From the viewpoint of regulating operativeness, stirring and reaction temperature, this reaction is preferably carried out in the presence of a solvent. The solvent used is not particularly limited insofar as it is inert to the hydrazide compound, halogenated acetate compound or base, and specifically it includes e.g. acetone, 2-butanone (MEK, methyl ethyl ketone), 3-pentanone (diethyl ketone), 3-hexanone (ethyl propyl ketone), 4-heptanone (dipropyl ketone), 2,4-dimethyl-3-pentanone (diisopropyl ketone), formamide, N,N-dimethyl formamide (DMF), tetrahydrofuran (THF), 1,2-dimethoxyethane (DME, ethylene glycol dimethyl ether), ethyl ether, isopropyl ether, butyl ether, methyl acetate, ethyl acetate, propyl acetate, methyl propionate, ethyl propionate, methyl butyrate, ethyl butyrate, dimethyl carbonate, diethyl carbonate, dipropyl carbonate, methyl ethyl carbonate, 1,4-dioxane, 1,3-dioxolane, nitromethane, 1-methyl-2-pyrrolidone, dimethyl sulfoxide (DMSO), hexamethyl phosphonamide (HMPA), acetonitrile, pyridine, triethylamine, N,N-dimethylaniline etc.
The reaction temperature is not limited, but usually by heating under reflux, the reaction is finished in a short time.
2. R2 is Introduced into a Heterodiazinon Compound Having the Substituent Group R1 (1) 
In the above scheme, A, R1, R2, R4 and R5 have the same meanings as defined above. In this reaction, a heterodiazinon compound is reacted with a halogen aryl compound, which can be conducted according to a conventional method in Ullmann reaction. Further, the reaction is conducted preferably in the presence of a base, and particularly potassium acetate gives better results. Further, this reaction can also be conducted by the coupling reaction of a heterodiazinon compound with an aryl boric acid compound using copper acetate in the presence of a base.
3. R2 is Introduced into a Heterodiazinon Compound Having the Substituent Group R1 (2) 
In this scheme, A, R1, R2, R4 and R5 have the same meanings as defined above. Also in this reaction, a heterodiazinon compound is reacted with a halogen aryl compound, which can be conducted according to a conventional method of N-alkylation in the presence of a base or in a usual manner by KOEN reaction.
4. When the Substituent Group R2 is a Lower Alkyl Group, an Imine is Reduced and then Cyclized 
In this reaction scheme, X represents a halogen atom, R represents hydroxyl group or a halogen atom, Ar represents an optionally substituted aryl group, and Rxe2x80x2 and Rxe2x80x3 are the same as or different from each other and each represents a lower alkyl group. In this reaction, an imine is synthesized from e.g. a benzoyl hydrazine compound and ketone, and then reduced and reacted with a halogenated acetate derivative, to give a heterodiazinon compound. The reducing agent used includes e.g. lithium aluminum hydride, sodium borohydride, sodium triacetoxysetoxy borohydride, sodium cyanoborohydride, etc.
In addition to the methods described above, the substituent groups R1 and R2 can also be modified to derive new compounds.
The foregoing is the process for producing Compound (I) etc. of the present invention, and the starting compound in the above reaction may have formed a salt or a hydrate insofar as the reaction is not inhibited. If the compounds of the present invention are obtained in free form, they can be converted in a usual manner into salts which may be formed by Compound (1) etc. The resulting various isomers of the compounds of the present invention can be isolated and purified by conventional separation techniques (e.g., re-crystallization, chromatography etc.).
As the pharmaceutical preparation, the compounds of the present invention, that is, the compound represented by the formula (I) below, a pharmacologically acceptable salt thereof or hydrates thereof and the heterodiazinon compound represented by the formula (V) below, a pharmaceutically acceptable salt thereof, as well as a composition comprising these, are useful as an agent for preventing, treating and ameliorating diseases against which non-N-methyl-D-aspartate excitatory antagonistic action is effective, specifically as an agent for preventing, treating and ameliorating diseases against which 2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid excitatory amino acid receptor antagonistic action is effective, more specifically as an agent for preventing, treating and ameliorating nerve degeneration diseases, and further specifically as an agent for preventing, treating and ameliorating 1) disturbance such as motor disturbance, hindrance of sensibility and abnormal behavior, caused by disturbance after cerebral ischemia and acute nerve degeneration after cerebrospinal injuries; 2) chronic nerve degeneration diseases such as Alzheimer""s disease, Parkinson""s disease, amyotrophic lateral sclerosis and Huntington""s chorea; 3) epilepsy; 4) chronic pain, migraine, cancerous pain and pain originating in diabetic nerve disturbance; 5) spastic paralysis or 6) demyelinating diseases such as multiple sclerosis, encephalomyelitis, Guillain Barre syndrome, Marchiafava Bignami disease, Devic disease, Balo disease, REFSAME disease, TANGIEL disease, DEJERIN-SOTAS disease, HIV or HTLV myelopathy, and leukoencephalopathy. 
In the formula, A represents oxygen, sulfur or a group represented by the formula  greater than NR3 (wherein R3 represents hydrogen atom or a lower alkyl group; R1 and R2 are the same as or different from each other and each represents an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl alkyl group, an optionally substituted aryl alkenyl group, an optionally substituted heteroaryl alkenyl group, an optionally substituted piperidyl group, an optionally substituted piperazinyl group, a morpholinyl group, an optionally substituted lower cycloalkyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, an adamantyl group, an optionally substituted amino group or an optionally substituted amide group; and R4 and R5 are the same as or different from each other and each represents hydrogen atom, hydroxyl group, a halogen atom, nitrile group, nitro group, a lower alkyl group, an aryl group or a heteroaryl group. 
In the formula, A represents oxygen, sulfur or a group represented by the formula  greater than NR3 (wherein R3 represents hydrogen atom or a lower alkyl group); and R1 and R2 are the same as or different from each other and each represents an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroaryl alkyl group, an optionally substituted aryl alkenyl group, an optionally substituted heteroaryl alkenyl group, an optionally substituted piperidyl group, an optionally substituted piperazinyl group, a morpholinyl group, an optionally substituted lower cycloalkyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, an adamantyl group, an optionally substituted amino group or an optionally substituted amide group.
The heterodiazinon compound (V) above encompasses compounds disclosed in the above-mentioned U.S. Pat. No. 4,670,555 (U.S. Pat. No. 4,782,066). Specifically, the heterodiazinon compound (V) includes the similar compound as described for the heterodiazinon compound (I).
Compound (I) according to the present invention can be formed in a usual manner into tablets, powders, fine powders, granules, coated tablets, capsules, syrups, troches, inhalations, suppositories, injections, ointments, eye ointments, eye drops, nose drops, ear drops, poultices and lotions. These pharmaceutical preparations are produced in a usual manner by blending generally used ingredients as starting materials, where ordinarily used excipients, binders, lubricants, coloring agents, taste and odor correctives and as a necessary stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives and antioxidants can be used for pharmaceutical manufacturing. That is, when an oral preparation is produced, the heterodiazinon compound or a pharmacologically acceptable salt thereof and excipients and as necessary a binder, an disintegrating agent, a lubricant, a coloring agent, taste and odor correctives etc. are added and formed in a usual manner into powders, fine powders, granules, tablets, coated tablets, capsules etc. These ingredients include e.g. animal and vegetable oils such as soybean oil, tallow and synthetic glyceride; hydrocarbons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicon resin; silicon oil; surfactants such as polyoxyethylene fatty ester, sorbitan fatty ester, glycerin fatty ester, polyoxyethylene sorbitan fatty ester, polyoxyethylene hardened castor oil and polyoxyethylene/polyoxypropylene block copolymer; water-soluble polymers such as hydroxy ethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinyl pyrrolidone and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyvalent alcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and sucrose; and inorganic powder such as silicic anhydride, aluminum magnesium silicate and aluminum silicate, and pure water. The excipients include e.g. lactose, corn starch, white sugar, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide etc.; the binder includes e.g. polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gumarabia, tragacanth, gelatin, shellac, hydroxypropyl methyl cellulose, hydroxy propyl cellulose, polyvinyl pyrrolidone, polypropylene glycol-polyoxyethylene block polymer, megulumin etc.; the disintegrating agent includes e.g. starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, carboxymethyl cellulose calcium etc.; the lubricant includes e.g. magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil etc.; the coloring agent includes e.g. those coloring agents approved to be added to pharmaceutical preparations; and the taste and odor correctives include cocoa powder, menthol, aromatic powder, peppermint oil, borneol, cinnamon powder etc. These tablets and granules may be coated as necessary. When the injection preparation is produced, a pH adjuster, a solubilizer and an isotonizing agent together with a solubilizing aid and a stabilizer as necessary may be added to the heterodiazinon compound or a pharmacologically acceptable salt thereof, which is then formed in a usual manner into an injection. An agent for external application can be produced in any conventional method. That is, the starting base material used in manufacturing can make use of various starting materials ordinarily used in pharmaceutical preparations, non-pharmaceutical preparations, cosmetics etc. Specifically, the starting base material includes e.g. animal and vegetable oils, mineral oil, ester oil, waxes, higher alcohols, fatty acids, silicon oil, surfactants, phospholipids, alcohols, polyvalent alcohols, water-soluble polymers, clay minerals, pure water etc. As necessary, a pH adjuster, an antioxidant, a chelating agent, a preservative, a coloring agent, a perfume etc. can further be added. However, the starting base material of the present agent for external application is not limited thereto. Further, ingredients having differentiation-inducing action, a blood-stream promoter, a sterilizer, an anti-inflammatory agent, a cell activator, vitamins, amino acids, a humectant, a keratin solubilizer etc. can also be incorporated as necessary. The amount of the starting base material added is usually an amount for achieving a concentration predetermined for producing the agent for external application.
When Compound (I) of the present invention is administered as a pharmaceutical preparation, it can be orally or parenterally administered in any form in a usual manner. For example, it can be formed into, and administered as, tablets, powders, granules, capsules, syrups, troches, inhalations, suppositories, injections, ointments, eye ointments, eye drops, nose drops, ear drops, poultices and lotions. Although the dose of the pharmaceutical preparation of the present invention is varied depending on the severeness of symptoms, age, sex, body weight, administration form and the type of disease, the pharmaceutical preparation is administered into a man in one portion or in divided portions in a daily dose of usually about 0.01 mg to 2000 mg, preferably 0.1 mg to 1000 mg, more preferably 0.5 mg to 500 mg.